This invention relates to the discovery that a group of peptidyl-aldehydes is useful in the inhibition of picornaviral 3C proteases.
Picornaviridae are a family of very small non-enveloped viruses having a core of capsid-enclosed positive-stranded RNA. The picornaviruses represent a wide variety of microbes which infect a broad range of animals, including humans. Examples of picornaviruses include rhinoviruses, enteroviruses (e.g. poliovirus, coxsackievirus, echovirus), cardioviruses (e.g. encephalomyocarditis virus, meningovirus), aphthoviruses (e.g. foot-and-mouth disease virus), and hepatistis A virus, among others.
In picornaviruses the RNA genome is translated into a single large viral polyprotein precursor. The precursor demonstrates auto-proteolytic activity, cleaving itself into mature viral gene products. Proteolytic cleavage, therefore, plays an important role in the regulation of picornavirus replication and may thus represent an ideal target for antiviral therapy of all picornaviruses, including human rhinoviruses.
Human rhinoviruses (HRVs) are one of the major causes of upper respiratory tract infections collectively known as the common cold. Despite considerable effort in identifying therapeutics for this malady, no safe and effective therapy is currently available. Perhaps the most recalcitrant problem plaguing researchers in the area is the propensity for these viruses to mutate and thus develop resistance to potential medicaments. Vaccine therapy proves to be problematic for this very reason, and chemotherapy appears to be the more desirable approach.
In the case of the human rhinoviruses, there are two proteolytic enzymes involved, namely 2A and 3C, both of which are believed to be sulfhydryl proteases. Since these viral enzymes have no known cellular counterparts, it may be possible to selectively inhibit these enzymes in the presence of host enzymes. That is, chemotherapeutic agents having activity directed against the viral proteases would not affect endogenous cellular enzymes.
It appears that members of the picornavirus family may all code for a substantially homologous viral 3C protease, and in all picornaviruses studied, 3C protease activity is required for the virus to undergo maturation. Based on experience with other virally encoded proteolytic enzymes such as HIV-1 protease, it is unlikely that the viruses will develop resistance to inhibitors of these proteases. Moreover, the highly conserved nature of the 3C enzyme itself and the natural pressures on the virus to retain this highly efficient means for replication mark the suitability of the protease as a target for therapy.
Therefore, compounds that inhibit the proteolytic activity of the 3C protease are particularly useful in treating picornaviral infections by interrupting the processing of the viral gene products into mature and infectious viral particles.